Polyamines are intimately linked to the growth of mammalian cells. Many changes in cellular metabolism induced by hormones and other agents are accompanied by marked increases in the rate of synthesis of putrescine and spermidine brought about by increases in the activities of ornithine decarboxylase and S-adenosylmethionine decarboxylase. The proposed experiments will extend knowledge of these enzymes which have interesting regulatory properties and very rapid apparent rates of synthesis and degradation. The mechanism of action of inhibitors of these enzymes will be investigated and the effects of administration of these inhibitors on polyamine metabolism and other cellular functions will be studied. The more detailed understanding of the levels of polyamines and derivatives in control and malignant cells in various physiological states and of the effects of inhibitors of polyamine synthesis will aid in the determination of the biological function of these compounds. The properties and turnover of S-adenosylmethionine decarboxylase will be investigated using enzyme purified to homogeneity by affinity chromatography and an antibody to the enzyme. An irreversible inhibitor, (1,1'((methylethanediylidene)-dinitrilo)-bis(3-aminoquanidine), of this enzyme has been synthesized and its mode of action and effects on polyamine levels will be studied. Purification of ornithine decarboxylase using affinity chromatography on N-(5-phosphopyridoxal)-ornithine bound to Sepharose will be used to carry out similar studies with this enzyme. It has been found that ornithine decarboxylase activity is reduced greatly on application of putrescine or of synthetic alpha, omega-diamines. The mechanism by which this inhibition is achieved and the possible synergistic effects of inhibitors of S-adenosylmethionine decarboxylase and the alpha, omega-diamines which reduce ornithine decarboxylase activity will be studied. Preliminary indications that these inhibitors may have selective effects on polyamine synthesis in different cell types will be investigated.